Project Summary/Abstract Alzheimer's disease (AD) is the only cause of death amongst the top ten in the United States which has no treatment. AD progression cannot be halted, and there are no disease-modifying drugs currently on the market (1). It is hypothesized that the reason many treatments have failed in the fight against AD is that once a person starts showing clinical cognitive decline, too many neurons are irreparably destroyed. Consequently, the prevailing notion in the field of AD research is that we must identify patients at risk for developing the disease, so we can treat them before symptoms manifest. In order to be successful in this endeavor, we must work to understand the etiopathogenesis of the disease. It is becomingly increasingly recognized that many cases of AD are multifactorial in nature; the most common mixed dementia pathology is standard AD amyloid and tau pathology in concert with vascular pathology. This proposal seeks to examine the relationship between vascular status, particularly arterial health metrics of the arteries of the Circle of Willis, and longitudinal metrics associated with AD progression, namely cognitive performance on neuropsychological tests and cerebrospinal fluid (CSF) analytes. Additionally, as AD is known to be genetically linked, this F30 project will also seek to investigate how differing genetic backgrounds interact with vascular and amyloid pathology. Specifically, this fellowship proposal will employ a newly developed 4D-Flow MRI method to characterize cerebrovascular disease in the major arteries of the brain. These metrics will be used as predictor variables in longitudinal linear mixed effects models to examine trajectories of cognitive decline. Furthermore, these arterial health metrics will be analyzed in concert with structural and molecular variables associated with AD, namely cortical atrophy, hippocampal atrophy, and CSF amyloid and tau, to determine whether poor vascular health is associated with a faster accumulation of AD-associated pathology. Lastly, a polygenic risk score representing the amyloid clearance pathway and metrics of arterial health will be studied in an interaction model to determine if optimal vascular health may be protective in those individuals with increased genetic risk for AD.